Chaperones

The last two decades of the twentieth century saw the discovery of the heat-shock or cell-stress response, changes in the expression of certain proteins, and the unraveling of the function of proteins that mediate this essential cell-survival strategy. The proteins made in response to the stresses are called heat-shock proteins, stress proteins, or molecular chaperones. A large number of chaperones have been identified in bacteria (including archaebacteria), yeast, and eukaryotic cells. Fifteen different groups of proteins are now classified as chaperones. Their expression is often increased by cellular stress. Indeed, many were identified as heat-shock proteins, produced when cells were subjected to elevated temperatures. Chaperones likely function to stabilize proteins under less than ideal conditions.

The term chaperone was coined only in 1978, but the existence of chaperones is ancient, as evidenced by the conservation of the peptide sequences in the chaperones from prokaryotic and eukaryotic organisms, including humans.

Chaperones function 1) to stabilize folded proteins, 2) unfold them for translocation across membranes or for degradation, or 3) to assist in the proper folding of the proteins during assembly. These functions are vital. Accumulation of unfolded proteins due to improper functioning of chaperones can be lethal for cells. Prions serve as an example. Prions are an infectious agent composed solely of protein. They are present in both healthy and diseased cells. The difference is that in diseased cells the folding of the protein is different. Accumulation of the misfolded proteins in brain tissue kills nerve cells. The result for the affected individual can be dementia and death, as in the conditions of kuru, Creutzfeld-Jakob disease and "mad cow" disease (bovine spongiform encephalopthy).

Chaperones share several common features. They interact with unfolded or partially folded protein subunits, nascent chains emerging from the ribosome, or extended chains being translocated across subcellular membranes. They do not, however, form part of the final folded protein molecule. Chaperones often facilitate the coupling of cellular energy sources (adenosine triphosphate; ATP) to the folding process. Finally, chaperones are essential for viability.

Chaperones differ in that some are non-specific, interacting with a wide variety of polypeptide chains, while others are restricted to specific targets. Another difference concerns their shape; some are donut-like, with the central zone as the direct interaction region, while others are block-like, tunnel-like, or consist of paired subunits.

The reason for chaperone's importance lies with the environment within cells. Cells have a watery environment, yet many of the amino acids in a protein are hydrophobic (water hating). These are hidden in the interior of a correctly folded protein, exposing the hydrophilic (water loving) amino acids to the watery interior solution of the cell. If folded in such a correct manner, tensions are minimized and the three-dimensional structure of the protein is stable. Chaperons function to aid the folding process, ensuring protein stability and proper function.

Protein folding occurs by trial and error. If the protein folds the wrong way, it is captured by a chaperone, and another attempt at folding can occur. Even correctly folded proteins are subject to external stress that can disrupt structure. The chaperones, which are produced in greater amounts when a cell is exposed to higher temperatures, function to stabilize the unraveling proteins until the environmental crisis passes.

Non-biological molecules can also participate as chaperones. In this category, protein folding can be increased by the addition of agents such as glycerol, guanidium chloride, urea, and sodium chloride. Folding is likely due to an electrostatic interaction between exposed charged groups on the unfolded protein and the anions.

Increasing attention is being paid to the potential roles of chaperones in human diseases, including infection and idiopathic conditions such as arthritis and atherosclerosis. One subgroup of chaperones, the chaperonins, has received the most attention in this regard, because, in addition to facilitating protein folding, they also act as cell-to-cell signaling molecules.

See also Proteins and enzymes